Transdermal therapeutic system with fentanyl or related substances

ABSTRACT

The invention relates to a transdermal therapeutic system (TTS), comprising a backing layer, which is permeable to the active ingredient, at least one matrix layer, comprising fentanyl or an active agent analogous to fentanyl, based on polyacrylate and a protective layer to be removed before usage, characterized in that the polyacrylate polymer is self-adhesive, free of carboxyl groups, has a saturation solubility for fentanyl of 3 to 20 wt. %, preferably of 4 to 12 and particularly of 5 to 10 wt. % and the layers contain at least 80% of the included active ingredient in a molecularly-dispersed, dissolved form.

Fentanyl and fentanyl-analogous substances such as sulfentanyl,carfentanyl, lofentanyl and alfentanyl are extremely efficaciousanalgesics. The requirement for only a low dose and theirphysicochemical properties such as the n-octanol/water partitioncoefficient, melting point and the molecular weight make possible thetransdermal administration of these substances in an efficacious amountand their pharmacokinetic properties such as the rapid metabolizationand the relatively narrow therapeutic index make transdermaladministration desirable.

In fact, a TTS containing fentanyl as active compound has been on themarket for some years. This system is a “reservoir system”. A reservoirsystem is understood here as meaning a system which contains the activecompound in a liquid or gelatinous preparation in a sachet formed froman impermeable film, which serves as a back layer, and an activecompound-permeable membrane, the membrane additionally being providedwith an adhesive layer for fixing the system to the skin. In thisspecific case, fentanyl is dissolved in a mixture of ethanol and water.Further details of this system can be taken from US patent specification4,588,580 or DE-C 35 26 339, which both contain a detailed description.

Reservoir systems, however, have the disadvantage that in the case of aleak in the reservoir sachet the active compound-containing reservoirfilling comes in contact with the skin over a wide area and the activecompound is absorbed in excessively high doses. This is very dangerous,especially in the case of fentanyl and its derivatives, since anoverdose very rapidly leads to respiratory depression and thereforefatal incidents. A number of such fatal or near-fatal incidents aredescribed in Clinical Pharmacokinet. 2000, 38(1), 59-89.

The object of this invention was now to make available a transdermaltherapeutic system containing fentanyl or fentanyl analogs, which offersthe user increased safety against an inadvertent absorption ofoverdoses.

This is possible according to the invention in that, instead of thereservoir system, a matrix system is employed in which the activecompound is incorporated directly into a self-adhesive polyacrylate andthus, even in the case of damage to the system, cannot come into contactwith the skin over a greater area than afforded by the TTS. In such asystem, the active compound is generally completely, but to at least80%, dissolved in molecularly disperse form in this polymer, thesaturation solubility of the active compound in the polymer beingbetween 3 and 20% by weight. Furthermore, it has surprisingly been shownthat when using polyacrylate adhesives for the production of TTScontaining fentanyl and its analogs, only adhesives without freecarboxyl groups are suitable.

Such matrix systems in the simplest case consist of a back layer, whichis impermeable to the active compound, of a self-adhesive activecompound-containing layer and of a protective layer to be removed beforeuse. In complicated embodiments of such systems is additionally alsoadded a membrane controlling the release of active compound, which isnormally further provided with an adhesive layer for fixing the systemto the skin.

The active compound-containing layers of such a matrix system accordingto this invention consist of polyacrylates. Since free functional groupsincrease the saturation solubility of fentanyl and its derivatives inpolyacrylate adhesives above the preferred range, the polyacrylateadhesives which are best suited are those which have no free functionalgroups and are only prepared from esters of acrylic and/or methaycrylicacid and optionally other vinyl compounds without free functional groupssuch as vinyl acetate. However, in the synthesis of the adhesive,monomers having free hydroxyl groups such as 2-hydroxyethyl acrylate or2-hydroxyethyl methacrylate can be tolerated up to a content of 20% byweight. Polyacrylates are prepared by free-radical polymerization usingacrylic and/or methacrylic acid derivatives. Such derivatives are, forexample, esters. By way of example of such derivatives, acrylic andmethacrylic acid derivatives may be mentioned, in particular esters ofalcohols having 1 to 8 C atoms, which optionally contain one hydroxylgroup, such as 2-ethylhexyl acrylate, n-octyl acrylate, propyl acrylate,n- or isobutyl acrylate, 2-hydroxyethyl acrylate and dimethylaminoethylacrylate or the corresponding methacrylates. Additionally, otherpolymerizable vinyl compounds without free functional groups such as,for example, vinyl acetate can also be used, e.g. in amounts of up to50% by weight. The polymers thus prepared are also described as randomcopolymers, as solely the quantitative distribution of the monomersemployed and chance decide the composition of the polymer chains.

If the polymers contain free hydroxyl groups, the possibility exists ofadditionally crosslinking the polymer chains by polyvalent cations suchas Al³⁺ or Ti⁴⁺ or reactive substances such as melamine. Use is made ofthis possibility in order to increase the molecular weight and thus toimprove the cohesion of the polymers. The possibility of thecrosslinkage of polyacrylates, in particular of polyacrylate adhesives,is particularly valuable if the plasticizing action of the activecompound dissolved in the polymers or the plasticizing action of otherauxiliaries has to be compensated. The adhesive is usually used in theform of a solution. Solvents used are, for example, ethyl acetate,hexane or heptane, ethanol or their mixtures. These are removed duringthe preparation of the TTS.

Table 1 shows the results of permeation studies which have been obtainedusing an adhesive with and an adhesive without free carboxyl groups (butwithout hydroxyl groups). In both adhesives, the active compound wasincorporated in a concentration of 5 percent by weight. The permeationstudy was carried out by means of the Franz diffusion cells known to theperson skilled in the art and using human skin.

TABLE 1 Results of permeation studies using adhesives with and withoutfree carboxyl groups Cumulated amount of permeated active compound[μg/cm²] Mean value of n = 3 * Formulation 4 h 8 h 24 h 48 h 72 h 1 0.000.00 0.44 1.71 3.51 2 0.0 0.2 4.0 14.7 28.24 * skin used: female lowerabdominal skin Formulation 1: polyacrylate adhesive with 4.8% by weightof free carboxyl groups Formulation 2: neutral polyacrylate adhesivewithout free carboxyl groups but with 5.2% by weight of free hydroxylgroups

The results show that a neutral adhesive without free carboxyl groups ismarkedly superior to a carboxyl group-containing adhesive with respectto the permeation rates achievable.

An important characteristic of each active compound-containing polymerin TTS technology is the saturation solubility of the chosen polymer forthe respective active compound. This parameter is important because thethermodynamic activity of the active compound in the matrix does notdepend on the absolute amount of active compound dissolved, but ratheron the ratio of the actual concentration to the saturationconcentration. Since the active compound on application of the TTS tothe skin must disperse in the skin and in the process bring into linenot concentrations, but activities, it is important for achieving apermeation rate which is as high as possible to choose as high aspossible a thermodynamic activity of the active compound in the TTS.This means that the solubility of the active compound in the activecompound-containing parts of the TTS must not be too high, sinceotherwise the active compound concentration in the TTS must be quitehigh in order to achieve an adequately high thermodynamic activity. Thisis unadvantageous if the active compound disadvantageously influencesthe physical properties of the active compound-containing parts of thesystem in the high concentration and/or the active compound is veryexpensive. In the case of fentanyl, both reasons are true, itadditionally still having to be taken into consideration that fentanyland its derivatives belong to the narcotics and for this reason alone itis therefore desirable to incorporate as little active compound in theTTS as possible and/or to make the utilization of active compound, i.e.the ratio of active compound released during the wearing time of the TTSto the content of the unworn TTS, as large as possible.

From this point of view, the saturation solubility of the activecompound-containing layers for a three-day TTS should not be below 3percent by weight and not above 20 percent by weight. At highersaturation solubilities, even with a high specific permeation rate, theutilization of active compound is too poor, and the TTS is not readilymarketable for commercial reasons because of the expensive activecompound. Preferably, for these reasons the saturation solubility isbetween 4 and 12 and particularly preferably between 5 and 10, percentby weight.

The saturation solubility of fentanyl and its analogs can additionallybe reduced by the addition of substances which do not have gooddissolving properties for the active compound. Such substances are, forexample, liquid hydrocarbons such as dioctylcyclo-hexane, liquidparaffin, hydrocarbon resins such as polyterpenes, in particularpolypinene, or polar substances such as glycerol, di- and triglycerol orpolyethylene glycols, e.g. having a molecular weight from 200 to 1000.These substances can form a homogeneous mixture with the polyacrylateadhesive or else be contained therein as a separate phase. Glycerol andits derivatives especially are already present in low concentrations inthe matrix as a separate phase, e.g. in the form of droplets. By meansof the addition of such substances, it is in particular also possible tocompensate the higher saturation solubility in adhesives having freehydroxyl groups.

Table 2 contains some data regarding the saturation solubilities offentanyl in some of these substances.

TABLE 2 Saturation solubilities of fentanyl in solubility-decreasingadditives Saturation solubility Substance [% by weight] Polyethyleneglycol 400 7.5 Glycerol <1.5 Diglycerol <1.5 Dioctylcyclohexane <1.9Paraffin, liquid <1.5

The influence of such additives can be recognized by means ofcomparative permeation studies.

In table 3, the results of permeation studies with matrices based on aneutral polyacrylate adhesive having free hydroxyl groups with andwithout such additives and of a polyacrylate adhesive without other freefunctional groups are compared. All formulations contain fentanyl in aconcentration of 5% by weight.

TABLE 3 Comparative permeation studies using formulations with andwithout solubility-decreasing additives Cumulated amount of permeatedactive compound [μg/cm²] Mean value of n = 3 * Formulation 4 h 8 h 24 h48 h 72 h 2 0.00 0.23 7.89 32.82 64.17 3 0.798 4.46 29.6 68.9 103.1 40.805 4.87 32.6 74.7 113.2 Formulation 2: 5% by weight fentanyl in aneutral polyacrylate adhesive with 5.2% free hydroxyl groups Formulation3: fentanyl 5.0% polyacrylate adhesive, neutral with 55.0% 5.2% freehydroxyl groups polypinene 15.0% glycerol 10.0% dioctylcyclohexane 15.0%Formulation 4: 5% by weight of fentanyl in a polyacrylate adhesivewithout free functional groups * skin: human epidermis, female breastskin

The results of the permeation study show that the permeation rate can besignificantly improved by the addition of substances reducing thesolubility of the active compound in the matrix. Approximately the sameresults are achieved by the use of an adhesive without free functionalgroups, which even without additives has a low dissolving capacity forthe active compound.

From the permeation data, the respective TTS sizes can be calculated forvarious TTS strengths. The results are listed in table 4.

TABLE 4 TTS sizes calculated from permeation data Calculated area sizes[cm²] Release rate Form. 1 Form. 2* Form. 2** Form. 3 Form. 4 25 μm/h513 63.7 28.1 17.45 15.9 50 μm/h 1026 127.4 56.2 34.9 31.8 75 μm/h 1539191.1 84.3 52.35 47.7 100 μm/h  2052 254.8 112.4 69.8 63.6 *calculatedon the basis of the permeation data from table 1 **calculated on thebasis of the permeation date from table 2

The result of the calculation shows that carboxyl group-containingadhesives at a fentanyl concentration of 5% even at the lowest dose leadto TTS which are too large for practical use. Although quite large TTSare also calculated in the case of the hydroxyl group-containingadhesives, the possibility exists here due to the increase in thefentanyl concentration to arrive at TTS having a size suitable forpractical use with concentrations which are not too high, i.e. at most20%. Simplified, it can be assumed here that the thermodynamic activityand thus also the permeation rates depend linearly on the concentration,as long as the active compound is present completely dissolved.

By use of the solubility-lowering auxiliaries in formulations havinghydroxyl group-containing polyacrylate adhesives or by the use ofpolyacrylate adhesives without free functional groups, even at afentanyl concentration of 5%, TTS are obtained which have an acceptablesize, even in the highest dose of 100 μg/h. Of course, the possibilityalso offers itself here of further reducing the system area byincreasing the fentanyl concentration.

Fentanyl and its derivatives, as already mentioned at the outset, have anarrow therapeutic index. This means that for the action, on the onehand, a certain threshold value which must be exceeded with respect tothe plasma concentration, on the other hand unacceptable side-effectsrapidly occur at higher concentrations. It is therefore advantageous ifthe system additionally contains a control membrane and thus the activecompound flow through the skin is restricted to a maximum valueindependently of the individual skin condition. Such membranespreferably consist of a copolymer of ethylene and vinyl acetate (EVApolymer) or are microporous films based on polyethylene orpolypropylene. The prior art includes membranes of this type. In thecase of the EVA polymers, the active compound permeability depends onthe content of vinyl acetate and the thickness of the membrane.Membranes having a VA content of between 2 and 25 percent by weight anda thickness of between 25 and 100 μm, preferably between 40 and 100 μm,are customary, there being scarcely any limitations in practice withrespect to the vinyl acetate content and the thickness. For theparticular formulation, both parameters must be chosen accordingly inorder to guarantee restriction to the desired maximum flow from the TTS.In the case of the microporous membranes, the substance transport doesnot take place through the polymer, but only through the pores found inthese membranes. The number and size of the pores in this casedetermines the maximum release rate of the TTS.

Customarily, such membranes are provided with an adhesive film forfixing the TTS to the skin. Adhesive films based on self-adhesivepolyacrylates or self-adhesive polysiloxanes are particularly suitablefor fentanyl and its derivatives. The advantage of poly-siloxanes hereis that the active compound in these polymers is very poorly soluble andtherefore the active compound loading of the TTS does not have to beincreased unnecessarily by the use of an additional adhesive film.Adhesive films of this type, however, can also be used in systems whichcontain no membranes, but matrix layers having lower adhesive power.

As in any TTS, of course, there is also the possibility here of reducingthe barrier properties of the human horny layer by the use ofpermeation-promoting substances. Such substances are, for example, fattyacids, fatty alcohols, fatty acid esters, esters of glycerol withmedium- or long-chain fatty acids and glycols such as 1,2-propanediol.All substances can be employed here which are physiologically acceptableand compatible with the active compound and the other excipients.

In summary, it is to be observed the matrix systems within the meaningof this invention show satisfactory to good permeation rates and alsomake possible the production of TTS having an acceptable size. At thesame time, an endangering of the patient by an excessively highabsorption of active compound as a result of a leak is impossible.Overall, matrix systems based on polyacrylate adhesives within themeaning of this invention are thus an important advance in relation tothe known prior art for fentanyl and its analogs with respect to patientsafety.

EXAMPLES Example 1 (Formulation 1, 2, 4)

Fentanyl (free base) is dissolved in the solution of the adhesive inheptane/ethyl acetate. The amount of fentanyl is in this case calculatedsuch that, based on the solids content of the adhesive solution, aconcentration of 5.0% results. The resulting material is coated using adoctor blade onto a siliconized polyester film protective layer to beremoved before use, in a thickness such that, after the removal of thesolvent, a weight of the coating of about 80 g/m² results. After theremoval of the solvent, the dried film is laminated with a thinpolyester film (back layer of the TTS), and the finished TTS are stampedout of the complete laminate.

Example 2 (Formulation 3)

5.0 g of fentanyl, 15.0 g of polypinene, 10.0 g of glycerol, 15.0 g ofdioctylcyclohexane and 110 g of the adhesive solution having a solidscontent of 50.0% are combined and stirred until the fentanyl hasdissolved.

The resulting material is coated using a doctor blade onto a siliconizedpolyester film (protective layer to be removed before use) in athickness such that, after the removal of the solvent, a weight of thecoating of about 80 g/m² results. After the removal of the solvent, thedried film is laminated with a thin polyester film (back layer of theTTS) and the finished TTS are stamped out of the complete laminate.

The invention claimed is:
 1. A transdermal therapeutic system (TTS)consisting of: A) an active compound-impermeable back layer; B) onematrix layer based on polyacrylate and comprising fentanyl; and C) aprotective film to be removed before use; wherein said polyacrylate: i)is self-adhesive; ii) is free of carboxyl groups, but has at least onehydroxyl group; iii) is prepared from a monomer mixture consisting of:a) esters of acrylic and/or methacrylic acid, which are esters ofalcohols having 1 to 8 carbon atoms; and b) 2-hydroxyethyl acrylate or2-hydroxyethyl methacrylate in amounts of up to 20% by weight; and iv)has a saturation solubility for fentanyl of between 5 and 20 percent byweight; and wherein said one matrix layer contains at least 80 percentby weight of the incorporated fentanyl in molecularly disperse dissolvedform.
 2. The transdermal therapeutic system (TTS) according to claim 1,wherein the esters of acrylic and/or methacrylic acid according to iiia) are selected from the group consisting of 2-ethylhexyl acrylate,n-octyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylateand the corresponding methacrylates.
 3. The transdermal therapeuticsystem (TTS) according to claim 1, wherein the fentanyl is present in aconcentration of at least 5% by weight in the matrix layer.
 4. Thetransdermal therapeutic system (TTS) according to claim 1, wherein thefentanyl is present in a concentration of at most 20% by weight in thematrix layer.
 5. The transdermal therapeutic system (TTS) according toclaim 1, wherein the fentanyl is completely dissolved in molecularlydisperse form in said polyacrylate.
 6. The transdermal therapeuticsystem (TTS) according to claim 1, wherein the polyacrylate containsfree hydroxyl groups that are crosslinked by Al³⁺ or Ti⁴⁺.
 7. Thetransdermal therapeutic system (TTS) according to claim 1, wherein thepolyacrylate has a saturation solubility for fentanyl of between 5 and12 percent by weight.
 8. The transdermal therapeutic system (TTS)according to claim 7, wherein the polyacrylate has a saturationsolubility for fentanyl of between 5 and 10 percent by weight.
 9. Thetransdermal therapeutic system (TTS) according to claim 1, wherein saidone matrix layer contain at least one substance which improves thepermeation rate through human skin, said substance being selected fromthe group consisting of glycols, fatty acids, fatty acid esters, fattyalcohols and glycerol esters.
 10. The transdermal therapeutic system(TTS) according to claim 1, wherein said one matrix layer contains atleast one substance which lowers the solubility of the active compound,said substance being selected from the group consisting of liquidhydrocarbons, liquid paraffin, hydrocarbon resins, polar substances andpolyethylene glycols having a molecular weight from 200 to
 1000. 11. Thetransdermal therapeutic system (TTS) according to claim 1, wherein theesters of acrylic and/or methacrylic acid according to iii a) areselected from the group consisting of 2-ethylhexyl acrylate, n-octylacrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate and thecorresponding methacrylates; wherein the polyacrylate contains freehydroxyl groups that are crosslinked by Al³⁺ or Ti⁴⁺; wherein fentanylis completely dissolved in molecularly disperse form in saidpolyacrylate; wherein the one matrix layer contains at least onesubstance which improves the permeation rate through human skin, saidsubstance being selected from the group consisting of glycols, fattyacids, fatty acid esters, fatty alcohols and glycerol esters; andwherein the one matrix layer contains at least one substance which lowerthe solubility of the active compound, said substance being selectedfrom the group consisting of liquid hydrocarbons, liquid paraffin,hydrocarbon resins, polar substances and polyethylene glycols having amolecular weight from 200 to
 1000. 12. A transdermal therapeutic system(TTS) consisting of: A) an active compound-impermeable back layer; B) atleast one matrix layer based on polyacrylate and comprising fentanyl;and C) a protective film to be removed before use; wherein saidpolyacrylate: i) is self-adhesive; ii) is free of carboxyl groups, buthas hydroxyl groups to effect crosslinking; iii) is prepared from amonomer mixture consisting of: a) esters of acrylic and/or methacrylicacid, which are esters of alcohols having 1 to 8 carbon atoms; and b)2-hydroxyethyl acrylate and/or 2-hydroxyethylmethacrylate; wherein eachmonomer is present in the monomer mixture; and iv) has a saturationsolubility for fentanyl of between 5 and 20 percent by weight; whereinsaid at least one matrix layer contains at least 80 percent by weight ofthe incorporated fentanyl in molecularly disperse dissolved form;wherein the amount of 2-hydroxyethyl acrylate and/or2-hydroxyethylmethacrylate is up to 20% by weight; and wherein saidpolyacrylate is crosslinked by polyvalent cations that are selected fromthe group consisting of Al³⁺ or Ti⁴⁺.
 13. The transdermal therapeuticsystem (TTS) according to claim 12, wherein the polyacrylate has asaturation solubility for fentanyl of between 5 and 12 percent byweight.
 14. The transdermal therapeutic system (TTS) according to claim13, wherein the polyacrylate has a saturation solubility for fentanyl ofbetween 5 and 10 percent by weight.
 15. The transdermal therapeuticsystem (TTS) according to claim 12, wherein said at least one matrixlayer contains at least one substance which lowers the solubility offentanyl, said substance being selected from the group consisting ofliquid hydrocarbons, liquid paraffin, hydrocarbon resins, polarsubstances and polyethylene glycols having a molecular weight from 200to
 1000. 16. The transdermal therapeutic system (TTS) according to claim13, wherein said at least one matrix layer contains at least onesubstance which lowers the solubility of fentanyl, said substance beingselected from the group consisting of liquid hydrocarbons, liquidparaffin, hydrocarbon resins, polar substances and polyethylene glycolshaving a molecular weight from 200 to
 1000. 17. The transdermaltherapeutic system (TTS) according to claim 14, wherein said at leastone matrix layer contains at least one substance which lowers thesolubility of fentanyl, said substance being selected from the groupconsisting of liquid hydrocarbons, liquid paraffin, hydrocarbon resins,polar substances and polyethylene glycols having a molecular weight from200 to 1000.